Is isolazine (isosorbide dinitrate) effective as a first-line treatment for patients with heart failure?

Isosorbide Dinitrate in Heart Failure: Not a First-Line Treatment

Isosorbide dinitrate (isolazine) should not be used as first-line monotherapy for heart failure; it is only recommended in combination with hydralazine for specific patient populations after optimization of guideline-directed medical therapy (ACE inhibitors/ARNIs, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors). 1

First-Line Therapy for Heart Failure with Reduced Ejection Fraction

The foundational therapies that should be initiated first include:

• Angiotensin receptor-neprilysin inhibitors (ARNIs), ACE inhibitors, or angiotensin receptor blockers (ARBs) as the cornerstone of neurohormonal blockade 1, 2
• Beta-blockers to attenuate ventricular remodeling and improve survival 1, 3
• Mineralocorticoid receptor antagonists (MRAs) to reduce sudden death risk 1, 3
• SGLT2 inhibitors as disease-modifying therapy 1, 2
• Diuretics for symptomatic relief of congestion 1

These medications should be started simultaneously at low doses and titrated to target, or sequentially based on clinical factors, without waiting to achieve target dosing before initiating the next medication. 1

When Isosorbide Dinitrate (Combined with Hydralazine) Is Appropriate

For African American Patients with Persistent Symptoms

The combination of hydralazine and isosorbide dinitrate is recommended (Class I) for self-identified African American patients with NYHA class III-IV HFrEF who remain symptomatic despite optimal therapy with ACE inhibitors/ARBs, beta-blockers, and MRAs. 1, 4

• This recommendation is based on the A-HeFT trial, which demonstrated reduced mortality and hospitalizations in this specific population 1
• The benefit was only seen at high doses: hydralazine 75 mg three times daily plus isosorbide dinitrate 40 mg three times daily 1, 5
• This provides high economic value in this population 1

For Patients Intolerant to First-Line Agents

Hydralazine-isosorbide dinitrate might be considered (Class IIb) in patients who cannot tolerate ACE inhibitors, ARNIs, or ARBs due to hypotension, renal insufficiency, hyperkalemia, cough, or angioedema. 1, 5

• However, the evidence for this indication is substantially weaker than for African American patients 1, 5
• Referral to a heart failure specialist is strongly recommended before using this combination in ACE inhibitor/ARB-intolerant patients 1, 6, 5
• Recent observational data have not confirmed benefit in this population 5

Use in Acute Heart Failure Syndromes

For acute decompensated heart failure with pulmonary edema:

• High-dose intravenous isosorbide dinitrate (3 mg IV every 5 minutes) combined with low-dose furosemide (40 mg IV) is more effective than low-dose nitrates with high-dose furosemide 1
• This regimen significantly reduced myocardial infarctions (37% vs 17%) and intubations (40% vs 13%) in severe acute heart failure 1
• Intravenous nitroglycerin significantly reduced in-hospital mortality compared to inotropic therapy with milrinone (OR 0.69) or dobutamine (OR 0.46) 1
• Nitrates should be titrated to the highest hemodynamically tolerable dose 1

However, hydralazine has unpredictable response and prolonged duration of action, making it less desirable for acute treatment of decompensated heart failure. 4 All major trials studied chronic oral therapy, not acute intravenous administration. 4

Critical Pitfalls to Avoid

• Never use hydralazine as monotherapy—it must be combined with isosorbide dinitrate for chronic HFrEF 6, 4
• Do not substitute hydralazine-isosorbide dinitrate for ACE inhibitors in patients tolerating them well, as compliance is poor and side effects are common 4
• Avoid in acute MI or active ischemia, as reflex tachycardia can provoke myocardial ischemia 4
• Nitrate tolerance develops rapidly (within 16-24 hours) with continuous high-dose intravenous administration, limiting effectiveness 1
• In severe renal impairment (GFR <30 mL/min), reduce hydralazine dose by 50% due to drug accumulation 5
• Monitor for drug-induced lupus with prolonged hydralazine use, which can involve the kidneys 5

Dosing and Titration for Chronic Therapy

When initiating the combination for appropriate indications:

• Start with hydralazine 25 mg three times daily plus isosorbide dinitrate 20 mg three times daily 5
• Target dose: hydralazine 75 mg three times daily plus isosorbide dinitrate 40 mg three times daily 1, 5
• Titrate every 2-3 weeks as tolerated, monitoring blood pressure, symptoms, and renal function 5
• Check creatinine and potassium at 2-3 days, then monthly for 3 months, then every 3 months 5

The benefit in clinical trials was only achieved at these higher doses, which are often not reached in clinical practice due to side effects and complexity of the regimen. 1